US3897423A - Amino substituted acylthio cephalosporins - Google Patents

Amino substituted acylthio cephalosporins Download PDF

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Publication number
US3897423A
US3897423A US337806A US33780673A US3897423A US 3897423 A US3897423 A US 3897423A US 337806 A US337806 A US 337806A US 33780673 A US33780673 A US 33780673A US 3897423 A US3897423 A US 3897423A
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Prior art keywords
lower alkyl
hydrogen
compound
phenyl
formula
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Expired - Lifetime
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US337806A
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English (en)
Inventor
Uwe D Treuner
Hermann Breuer
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ER Squibb and Sons LLC
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ER Squibb and Sons LLC
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Priority to US337806A priority Critical patent/US3897423A/en
Priority to GB84274A priority patent/GB1452692A/en
Priority to DE19742408905 priority patent/DE2408905A1/de
Priority to JP49026151A priority patent/JPS49124095A/ja
Priority to FR7407397A priority patent/FR2220251B1/fr
Application granted granted Critical
Publication of US3897423A publication Critical patent/US3897423A/en
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids

Definitions

  • R is hydrogen, lower alkyl, aralkyl, tri(lower alkyl)silyl, tri(lower alkyl)stannyl, a salt forming ion or the group
  • R is hydrogen, lower alkyl, aryl or certain heterocyclic groups
  • R and R each is hydrogen, lower alkyl or phenyl
  • R is lower alkyl, aryl or aralkyl
  • R is hydrogen or lower alkyl
  • R is hydrogen or lower alkyl; or together R and R complete certain nitrogen heterocyclics
  • X is hydrogen, hydroxy, azido, lower alkanoyloxy, lower alkoxy, lower alkylthio, lower alkylthiadiazolythio, the radical of a nitrogen base. or together X and R represent a bond linking carbon and oxygen in a lactone ring
  • n is l. 2 or 3; are useful as antibacterial agents.
  • R represents hydrogen, lower alkyl, aralkyl, tri(lower alkyl)silyl, tri(lower alkyl)stannyl, a salt forming ion or the group
  • R representshydrogen, lower alkyl, aryl or certain heterocyclic groups
  • R and R each is hydrogen, lower alkyl or phenyl
  • R represents lower alkyl, aryl or aralkyl
  • R is hydrogen or lower alkyl
  • R is hydrogen or lower alkyl or R and R together complete certain nitrogen heterocyclics and n is l, 2 or 3.
  • X is hydrogen, hydroxy, azido, lower alkanoyloxy, lower alkoxy, lower alkylthio, lower alkylthiadiazolylthio, the radical of a nitrogen base, or together X-and Rfrepresent a bond linking carbon and oxygen in a lactone ring.
  • R is hydrogen, alkali metal or especially hydrogen, methyl, pivaloyloxy, sodium or potassium;
  • R is hydrogen, phenyl, thienyl, fury] or. isothiazolyl, especially hydrogen or 'phenyl;
  • R and R each is hydrogen or lower alkyl','especially each is hydrogen, and methyl or ethyl when one or both is lower alkyl;
  • R is lower alkyl, preferably methyl or t-butyl;
  • R and R each is lower alkyl;
  • n is l or 2, especially 1; and
  • X is preferably hydrogen or acetoxy.
  • the lower alkyl groups are straight or branched chain hydrocarbon radicals having one to eight carbons in the chain, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl or the like.
  • the lower alkoxy and lower alkylthio groups include similar radicals.
  • the aryl groups are phenyl and simply substituted phenyl having one to three substituent groups. This includes phenyl and simply substituted phenyl bearing one to three substituents R1 (Preferably only one), such as the halogens (chlorine and bromine -being preferred), lower alkyl groups such as those defined above, lower alkoxy groups, hydroxy or carboxy. In the case of the last two named substituents there is preferably only one, especially in the para position of the phenyl.
  • Illustrative are phenyl, 0-, mand p-chlorophenyl, o-, mand p-bromophenyl, 3,4-dichlorophenyl, 3,5- dibromophenyl, o-, mand p-tolyl, p-methoxyphenyl, 3,4,5-trimethoxyphenyl, p-hydroxyphenyl, pcarboxyphenyl and the like.
  • the aralkyl groups include phenyl and phenyl attached to a lower alkyl group, including substituted phenyl rings,all as defined above.
  • Illustrative are benzyl, o-, mor p-chlorobenzyl, o-, mor p-bromobenzyl, o-, m- I or p' methylbenzyl, phe'nethyl, pchlorophenethyl, 3,5-diethylbenzyl, 3,4,5- trichlorobenzyl and the like.
  • the lower alkanoyloxy groups represented by X include the acyl group of acid esters.
  • the lower alkano'yl radicals are the acyl radicals of lower fatty acids containing alkyl radicals of the type described above.
  • the lower alkanoyloxy groups include, for example, acetoxy, propionyloxy, butyryloxy and the like.
  • X also represents the radical of an amine, e.g., a lower alkylamine like methylamine, ethylamine,dimethylamine, triethylamine, phenyl-lower alkylamine like dibenzylamine,
  • X and R may also join together, as indicated above, to form a bond linking carbon ando rygen in a lactone ring.
  • the heterocyclic groups represented by R are pyridyl, thienyl, furyl and isothiazolyl, as well as these heterocyclics with one or two of the substituents (R lhalo, lower alkyl (particularly methyl and ethyl), lower alkoxy (particularly methoxy and ethoxy) or phenyl.
  • R and R together with the nitrogen to which they are attached may also form a heterocyclic, i.e., piperidino, morpholino, thiamorpholino or piperazino and these too may bear one or two of the substituents (R re ferred to above.
  • the .salt forming ions represented by .R are metal ions, e.g.,: aluminum, alkali metal ions such as sodium or potassium, alkaline earth metal ions such as calcium or magnesium;or an amine salt ion, of which a number are known for this purpose, for example, phenyl-lower alkylamines like 5 dibenzylamine, N,N- diben'zylethylenediamine, lower alkylamines like methylamine, triethylamine, procaine, lower alkylpiperidines like N-ethylpiperidine, etc.
  • metal ions e.g.,: aluminum, alkali metal ions such as sodium or potassium, alkaline earth metal ions such as calcium or magnesium;or an amine salt ion, of which a number are known for this purpose, for example, phenyl-lower alkylamines like 5 dibenzylamine, N,N- diben'zylethylenediamine, lower alkyl
  • ester forming tri(lower alkyl)silyl and tri(lower alkyl)stannyl groups include, for example, trimethylsilyl, triethyl'silyl, tri-nbutylstannyl and the like.
  • the new acylthiocephalosporins of the invention are produced by reacting a 7-aminocephalosporanic acid compound of formula II [which includes particularly 7-aminocephalospo ranic acid (7-ACA and 7-amino-3- desacetoxycephalosporanic acid (7-ADCA)], or an activated derivative thereof, of the formula with an acid of the formula
  • the activated derivatives refered to include, for example, the reaction product with an anhydride forming reagent such as ethylchloroformate, benzoyl chloride, pivaloyl chloride, etc., or with bis-imidazolecarbonyl, dicyclohexylcarbodiimide, p-nitrophenol or the like.
  • the reaction between the 7-aminocephalosporanic acid compound and the acid may be effected, for example, by dissolving or suspending the latter in an inert organic solvent such as chloroform, methylene chloride, dioxane, benzene or the like, and adding, at about room temperature or below, about an equimolar amount of an anhydride forming reagent, e.g., ethyl chloroformate, benzoylchloride or the like, or other activating compound such as dicyclohexylcarbodiimide, along with a salt forming organic base, such as triethylamine, pyridine or the like, followed, after an interval, by the addition of the 7-aminocephalosporanic acid compound.
  • an inert organic solvent such as chloroform, methylene chloride, dioxane, benzene or the like
  • an anhydride forming reagent e.g., ethyl chloroformat
  • the product of the reaction is then isolated by conventional procedures, e.g., by concentration or evaporation of the solvent.
  • Other known methods involving mixed anhydrides, activated esters or amides, isoxazolium salts, etc. may also be utilized.
  • R is the acyloxymethyl group with a compound of the formula R]CH-CO-NH(
  • Me represents a metal, hal is halogen, preferably chlorine or bromine and all the other symbols are the same as above.
  • Certain of the compounds of this invention may exist in different optically active forms.
  • the various stereoisomeric forms as well as the diastereoisomeric mixtures are within the scope of the invention.
  • the compounds of this invention have a broad spectrum of antibacterial activity against both gram positive and gram negative organisms such as Staphylococcus aureus, Salmonella schottmuelleri, Pseudomonas aerugiphenylacetamido)cephalosporanic acid and 0.8 g. (5 mmol.) of (dimethylamino)thioacetic acid S-potassium salt in 20 ml. of dimethylformamide are stirred for 30 minutes at room temperature, then poured into ice nosa, Proteus vulgaris, Escherichia coli and Streptococ- 5 water and extracted with 3 X 50 ml. of ethyl acetate. cus pyogenes.
  • the organic phase is dried and the solvent driven off to in a prophylactic manner, e.g., in cleaning or disinfectgive DL-7-[2-[ [(dimethylamino)acetylJthio1-2- ing compositions, or otherwise to combat infections phenylacetamido]cephalosporanic acid, m.p. 141. due to organisms such as those named above, and in general may be utilized in a manner similar to cephalo- 10 thin andf gather lcelphalosprprinsl. For lpxample, a con?
  • EXAMPLE 2 poun o ormu a or a p ysio ogica y acceptable sa t I thereof may be used in various animal species in an 7'[2"[[(dlmethylanzmo)acetymhlghcetamldolceph' amount of about 1 to 200 mg/kg., daily, orally or parena osporamc terally, in single or two to four divided doses to treat in- By substituting 2 g. (5 mmol.) of 7-(2-bromo-2- fections of bacterial origin, e.g., 5.0 mg./kg. in mice.
  • phenylacetamido)cephalosporanic acid in the proce- Oral forms give prompt high blood-levels which are dure of Example 1, 7-[2- maintained for relatively long periods.
  • a physiologically acceptable salt thereof may be incorporated in an oral dosage form such as tablets, capsules or elixirs or in an injectable formin a sterile aqueous EXAMPLE 3 vehicle prepared according to conventional pharma- DL 7 [[(dimethy]amino)aety]]thio] 2 ceutlcal practlce- I phenylacetamido]-3-desacetoxycephalosporanic acid They may also be used in cleaning or d sinfecting y Substituting 7 (2 bromo z phenylacetamido) 3 f gi g g i aggg t sgi g 6 g 322 g; desacetoxycephalosporanic acid for the 7-(2-bromo-2- 0 y phenylacetamido)cephalosporanic acid in the proceof such compounds admixed vvlth, suspended or d1sdure of Example
  • the potassium salt is obtained by treating the free
  • the following examples are illustrative of the invenacid with an equivalent amount of potassium carbom tion. All temperatures are on the Centigrade scale. Adate dmonal vanatpns may b grodllced m same i The following additional products having the formula ner by appropriate substitution n the starting material. (c) in the table are obtained by the procedure of Exam;
  • EXAMPLE 1 pie 2 by substituting for the 7-a- (bromophenylacetamido)cephalosporanic acid, the 1 :aigg g ggigz figgl fgg3222; starting material (a), and for the (dimethylamino)thip e v p p 40. oacetic acid salt, the starting material (b) with the sub- 2.35 g. (5 mmol.) of 7-(2-br0mO-2 stituents indicated in the table:
  • O CH OE-R R is phenyl, R and R each is hydrogen or lower alkyl,
  • R R and R each is lower alkyl, n is l or 2 and X is hydrogen or acetoxy.
  • R, R- R and X each is hydrogen, R and R, each is lower alkyl.
  • each lower alkyl group is methyl and n is l.
  • R, R, and R each is hydrogen, R and R each is lower alkyl and X is acetoxy.
  • each lower alkyl group is methyl and n is l.
  • R, R R, and R each is hydrogen, R and R each is lower alkyl and X is acetoxy.
  • each lower alkyl group is methyl and n is l.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Fodder In General (AREA)
US337806A 1973-03-05 1973-03-05 Amino substituted acylthio cephalosporins Expired - Lifetime US3897423A (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US337806A US3897423A (en) 1973-03-05 1973-03-05 Amino substituted acylthio cephalosporins
GB84274A GB1452692A (en) 1973-03-05 1974-01-08 Amino substituted acylthio cephalosporins
DE19742408905 DE2408905A1 (de) 1973-03-05 1974-02-25 Aminoacylthiocephalosporine
JP49026151A JPS49124095A (enrdf_load_stackoverflow) 1973-03-05 1974-03-05
FR7407397A FR2220251B1 (enrdf_load_stackoverflow) 1973-03-05 1974-03-05

Applications Claiming Priority (1)

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US337806A US3897423A (en) 1973-03-05 1973-03-05 Amino substituted acylthio cephalosporins

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JP (1) JPS49124095A (enrdf_load_stackoverflow)
DE (1) DE2408905A1 (enrdf_load_stackoverflow)
FR (1) FR2220251B1 (enrdf_load_stackoverflow)
GB (1) GB1452692A (enrdf_load_stackoverflow)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3971780A (en) * 1975-02-19 1976-07-27 E. R. Squibb & Sons, Inc. Thio-β-lactam cephalosporins
US4029782A (en) * 1975-04-28 1977-06-14 Eli Lilly And Company Cefazolin suspension for parenteral administration

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3741962A (en) * 1971-05-21 1973-06-26 Squibb & Sons Inc Alpha-thioureidocephalosporanic acid compounds

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE788812A (fr) * 1971-09-14 1973-03-14 Squibb & Sons Inc Penicillines et cephalosporines thioacetylees, leur preparationet leursutilisations therapeutiques

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3741962A (en) * 1971-05-21 1973-06-26 Squibb & Sons Inc Alpha-thioureidocephalosporanic acid compounds

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3971780A (en) * 1975-02-19 1976-07-27 E. R. Squibb & Sons, Inc. Thio-β-lactam cephalosporins
US4029782A (en) * 1975-04-28 1977-06-14 Eli Lilly And Company Cefazolin suspension for parenteral administration

Also Published As

Publication number Publication date
DE2408905A1 (de) 1974-09-19
FR2220251B1 (enrdf_load_stackoverflow) 1977-03-11
JPS49124095A (enrdf_load_stackoverflow) 1974-11-27
FR2220251A1 (enrdf_load_stackoverflow) 1974-10-04
GB1452692A (en) 1976-10-13

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